Tatsuya Kaji1, Osamu Yamasaki1, Minoru Takata2, Masaki Otsuka3, Toshihisa Hamada4, Shin Morizane4, Kenji Asagoe5, Hiroyuki Yanai6, Yoji Hirai4, Hiroshi Umemura4, Keiji Iwatsuki7. 1. Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Melanoma Center, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. 2. Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Okada Orthopedics and Dermatology Clinic, 39-1 Kamigori, Hyogo, 678-1225, Japan. 3. Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Division of Dermatology, Shizuoka Cancer Center, 1007 Nagaizumi-cho, Shizuoka, 411-8777, Japan. 4. Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. 5. Department of Dermatology, National Hospital Organization Okayama Medical Center, 1711-1 Tamasu, Kita-ku, Okayama, 701-1154, Japan. 6. Department of Diagnostic Pathology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Melanoma Center, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. 7. Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Melanoma Center, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan. Electronic address: keijiiwa@cc.okayama-u.ac.jp.
Abstract
BACKGROUND: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared. RESULTS: Of 77 tissue samples, BRAF V600E was detected in 21 samples (27%), CDK4 R24C in 7, EPHB6 G404S in 6, BRAF V600K in 2, NEK10 E379K in 2, and CDK4 R24H, NRAS Q61K, NRAS Q61R, KRAS G12A, KIT L576P, KIT V559A, ERBB4 E452K, and PDGFRA E996K in one sample each. No driver mutations related to the MAPK cascade including RAS and BRAF were detected in the chronically sun-damaged (CSD) group of melanoma. Dual or triple driver mutations were found in four of 40 (10%) samples from the primary melanomas, and three of 37 (8%) of the metastatic melanomas. Fourteen of 26 (54%) samples of non-CSD melanoma, and 3 of 6 (50%) melanomas of unknown primary origin had the BRAF V600E mutation. Mutations in membrane-bound receptors including KIT, ERBB4 and EPHB6 were detected in 8 of 77 (10%) samples. Of 17 pairs of primary and metastatic melanomas from the same patient, the primary mutation pattern was changed to a novel one in three cases, and only one of the plural mutations in the primary melanoma was found in the metastatic lesions in two cases. CONCLUSIONS: BRAF V600E is a predominant mutation in non-CSD melanoma and melanomas of unknown primary origin. Mutational heterogeneity may exist in the primary melanoma (intra-tumor heterogeneity), and between the primary and metastatic lesions (inter-tumor heterogeneity).
BACKGROUND: Searching for driver mutations in melanoma is critical to understanding melanoma genesis, progression and response to therapy. OBJECTIVES: We aimed to investigate the frequency and pattern of driver mutations in Japanese primary and metastatic melanomas including cases of unknown primary origin, in relation to their clinicopathologic manifestations. METHODS: Seventy-seven samples from 60 patients with melanoma were screened for 70 driver mutations of 20 oncogenes by Sequenom MelaCarta MassARRAY, and the results for primary and metastatic melanomas were compared. RESULTS: Of 77 tissue samples, BRAFV600E was detected in 21 samples (27%), CDK4R24C in 7, EPHB6G404S in 6, BRAFV600K in 2, NEK10E379K in 2, and CDK4R24H, NRASQ61K, NRASQ61R, KRAS G12A, KITL576P, KITV559A, ERBB4E452K, and PDGFRA E996K in one sample each. No driver mutations related to the MAPK cascade including RAS and BRAF were detected in the chronically sun-damaged (CSD) group of melanoma. Dual or triple driver mutations were found in four of 40 (10%) samples from the primary melanomas, and three of 37 (8%) of the metastatic melanomas. Fourteen of 26 (54%) samples of non-CSD melanoma, and 3 of 6 (50%) melanomas of unknown primary origin had the BRAFV600E mutation. Mutations in membrane-bound receptors including KIT, ERBB4 and EPHB6 were detected in 8 of 77 (10%) samples. Of 17 pairs of primary and metastatic melanomas from the same patient, the primary mutation pattern was changed to a novel one in three cases, and only one of the plural mutations in the primary melanoma was found in the metastatic lesions in two cases. CONCLUSIONS:BRAFV600E is a predominant mutation in non-CSD melanoma and melanomas of unknown primary origin. Mutational heterogeneity may exist in the primary melanoma (intra-tumor heterogeneity), and between the primary and metastatic lesions (inter-tumor heterogeneity).
Authors: Talita Diniz Melo-Hanchuk; Mariana Bonjiorno Martins; Lucas Leite Cunha; Fernando Augusto Soares; Laura Sterian Ward; José Vassallo; Jörg Kobarg Journal: BMC Cancer Date: 2020-01-06 Impact factor: 4.430
Authors: Lazaro Hiram Betancourt; Jeovanis Gil; Yonghyo Kim; Viktória Doma; Uğur Çakır; Aniel Sanchez; Jimmy Rodriguez Murillo; Magdalena Kuras; Indira Pla Parada; Yutaka Sugihara; Roger Appelqvist; Elisabet Wieslander; Charlotte Welinder; Erika Velasquez; Natália Pinto de Almeida; Nicole Woldmar; Matilda Marko-Varga; Krzysztof Pawłowski; Jonatan Eriksson; Beáta Szeitz; Bo Baldetorp; Christian Ingvar; Håkan Olsson; Lotta Lundgren; Henrik Lindberg; Henriett Oskolas; Boram Lee; Ethan Berge; Marie Sjögren; Carina Eriksson; Dasol Kim; Ho Jeong Kwon; Beatrice Knudsen; Melinda Rezeli; Runyu Hong; Peter Horvatovich; Tasso Miliotis; Toshihide Nishimura; Harubumi Kato; Erik Steinfelder; Madalina Oppermann; Ken Miller; Francesco Florindi; Qimin Zhou; Gilberto B Domont; Luciana Pizzatti; Fábio C S Nogueira; Peter Horvath; Leticia Szadai; József Tímár; Sarolta Kárpáti; A Marcell Szász; Johan Malm; David Fenyö; Henrik Ekedahl; István Balázs Németh; György Marko-Varga Journal: Clin Transl Med Date: 2021-07